DESCRIPTION: In this proposal, the investigators have divided the project into three main groups of experiments. The bulk of the experiments will analyze the role of both endogenous and exogenous nitric oxide in small rodent and large mammal models of ischemia reperfusion injury of the lung. In the first phase, they will use two mouse knock-out models, one deficient in iNOS and the other eNOS. These models have already been established by one of the co-investigators. The co-investigators have utilized this model to address the role of endogenous nitric oxide in LPS induced injury. In this proposal, lung ischemia reperfusion will be studied in the genetically altered and in wild type mice. In the second phase of these experiments, the investigator will determine the effects of exogenous nitric oxide provided as inhaled NO and by NO donor (nitroprusside) on tolerance to ischemia. Their hypothesis is that exogenous NO in endothelial cells is protective from ischemia and reperfusion injury. However, its effects on alveolar epithelial cells is more complex and unpredictable. In the last set of experiments, in this phase, the investigators will test interventions aimed at altering cyclic GMP levels in the lung to determine the role of this second messenger in the vaso-regulatory response during reperfusion. In the second set of experiments, the effect of high potassium concentrations in the lung perfusion solution during ischemia will be evaluated. The investigators have preliminary data demonstrating the high potassium concentrations have detrimental effects on endothelial cell function, lung compliance, and gas transfer characteristics. In these experiments they will attempt to reverse the vaso-constrictor effects of potassium using nitroprusside and prostaglandin E1 to test the hypothesis that if vaso constriction from potassium is prevented, improved lung protection and lower pulmonary vascular resistance will be achieved similar to that seen in other organs, such as, kidney and liver. In the third phase of the project, experiments will address the problem of high flow reperfusion in patients with single lung transplantation by first determining the interactions between high potassium flush during ischemia and high flow reperfusion, testing the effects of modified reperfusion using progressively increasing flow rates during the first 30 minutes of reperfusion.